Examination of the D2/5-HT2 Affinity Ratios of Resolved 5,6,7,8,9,10-Hexahydro-7,10-iminocyclohept[b]indoles: An Enantioselective Approach toward the Design of Potential Atypical Antipsychotics

Richard E. Mewshaw, Mary E. Abreu, Lisa S. Silverman, Rose M. Mathew, Carol W. Tiffany, Michael A. Bailey, E. William Karbon, John W. Ferkany, Carl Kaiser

Research output: Contribution to journalArticlepeer-review

Abstract

Enantiomers of several N-substituted 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[6]indoles were obtained by the resolution of 2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole and 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole followed by N-alkylation. These, as well as the racemates, were evaluated for their affinity for the 5-HT2 and D2 receptors. Those compounds possessing the 7S,10R stereochemistry were consistently recognized by the 5-HT2 and D2 receptors as the eutomer. 2-Fluoro-11-[4-(4-fluorophenyl)-4-oxobutyl]-5,6,7,8,9,10-hexahydro-7S,10R-iminocyclohept[b]indole [(7S,10R)-8] had the highest affinity for the 5-HT2 receptor (Ki = 0.80 nM), while its distomer (7R,10S)-8 was the most selective member of this class of bridged γ-carbolines (D2/5-HT2 = 562). Incorporation of a benzoyl or isosteric benzisoxazole moiety tethered by a four-carbon spacer to a bridged γ-carboline nucleus, possessing the 7S,10R absolute configuration, produced high affinity ligands for the 5-HT2 and D2 receptors.

Original languageEnglish (US)
Pages (from-to)3073-3076
Number of pages4
JournalJournal of medicinal chemistry
Volume36
Issue number21
DOIs
StatePublished - Jan 1 1993

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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